THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OF AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEAD ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE APPLICATION BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. This proposal describes applications of tandem, stereoselective hydroxyl- directed syn-oxidative cyclizations of acyclic hydroxypolyenes to polycyclic ethers. A variety of stereochemically complex bioactive natural products are targeted. This syn-oxidative cyclization strategy is stereocomplementary to known hydroxyl-directed epoxidation / anti- cyclization methodology, and potentially represents a biomimetic strategy for polycyclic ether synthesis based on consideration of a novel but untested tandem syn-oxidative cyclization hypothesis for polyether biosynthesis. Specific objectives include (1) asymmetric synthesis of polyene precursors for the efficient preparation of several structural types of antitumor acetogenin natural products, specifically gigantetrocin A and B, goniothalamicin, gigantecin, bullatacin, squamocin, and goniocin; (2) preparation of an all-(Z)-"premonensin" triene which will undergo a sequence of stereoselective syn-dihydroxylations and syn-oxidative cyclizations in a synthesis of the ionophore antibiotic monensin; and (3) exploration of syn-oxidative endocyclization modes, including synthesis of fused polyether natural products such as the neurotoxic, ion-channel activator represented by hemibrevetoxin B. The proposal is based on successful results with syn-oxidative polycyclizations of hydroxydienes and -trienes. Acylperrhenates have been, discovered to be generally high-yielding, stereoselective oxidizing reagents for the synthesis of five- and six-membered ring cyclic ethers from acyclic hydroxyalkenes. The synthetic concept of tandem oxidative polycyclization described herein will provide much shorter and more practical synthetic routes to several structural types of bioactive polycyclic ethers and their analogs. This research may also provide insights on pathways for polycyclic ether biosynthesis.